GENERATING OF ALLOREACTIVE CD4+T TRANSGENIC MICE

描述：逐字摘自申请人摘要）此R21试点应用 提出开发分析同种异体反应性T细胞的新型动物模型， 通过产生特异性CD4+ T细胞受体转基因小鼠， 供体抗原呈递细胞（“直接”）或由 宿主抗原呈递细胞（“间接”）。CD4+ T细胞发挥重要作用 对同种异体胰岛移植的免疫力以及 诱导对这种移植物的耐受性。CD4 T细胞参与的性质 这些免疫反应尚不清楚，但对于确定疾病进展至关重要。 临床胰岛移植治疗胰岛素依赖型糖尿病， 长期受者免疫抑制。CD4+ T细胞在免疫中的作用 同种异体移植免疫可能与CD8+ T细胞协同作用， 它们介导同种异体移植排斥反应的能力，或者它们可能有助于 通过向B细胞提供帮助而产生移植物特异性抗体应答。 或者，CD4+ T细胞可以作为效应细胞，对 同种异体组织通过两种不同途径之一：1）“直接” （供体MHC限制性）途径，其中CD4 T细胞与MHC II类相互作用 由供体APC表达的抗原或2）“间接”（宿主MHC限制性） 在这一途径中，它们与由抗原处理和呈递的移植物抗原相互作用， 在II类MHC抗原的背景下的宿主APC。有了这些不同的潜力 功能，CD4+ T细胞在同种异体移植免疫中或 耐受性诱导仍不确定。 同种异体反应性CD8+ T细胞受体（TCR）转基因小鼠模型具有 在解剖CD8 T细胞的作用方面表现出巨大的价值， 免疫应答，如阳性和阴性选择，对 外周抗原、自身免疫和肿瘤免疫。目前没有 同种异体反应性CD4+ TCR转基因小鼠。因此，具体目标 该项目的主要目的是建立携带CD4+ T细胞的TCR转基因小鼠 通过1）“直接”（供体APC依赖性）和2）“间接”（宿主 APC依赖的）同种异体抗原呈递途径。这种同种异体反应性CD4+ TCR 转基因动物将为我们提供一种可再生的直接和 已知特异性的间接效应T细胞，其中CD4+ T细胞的作用 细胞在已建立的胰岛移植排斥和耐受模型中， 定义了它们将允许对以下假设进行批判性评价： 胰岛同种异体移植免疫和耐受依赖于CD4 T细胞， 通过间接宿主MHC限制性抗原识别移植物抗原 演示文稿.

DESCRIPTION: Verbatim from the applicant's abstract) This R21 pilot application proposes to develop novel animal models of analyzing alloreactive T cells through the generation of CD4+ T cell receptor transgenic mice specific for either donor antigen presenting cells ('direct') or alloantigens presented by host antigen-presenting cells ('indirect'). CD4+ T cells play an essential role in immunity to allogeneic pancreatic islet transplants as well as in the induction of tolerance to such grafts. The nature of CD4 T cell involvement in these immune responses is unclear but critical to determine for the progression of clinical islet transplantation for IDDM without the current need for long-term recipient immunosuppression. Potential roles of the CD4+ T cell in allograft immunity may be in the collaboration with CD8+ T cells, facilitating their ability to mediate allograft rejection or they could contribute to the production of a graft-specific antibody response by supplying help to B cells. Alternatively, CD4+ T cells can function as effector cells, sensitized to allogeneic tissues through either of two distinct pathways: 1) a 'direct' (donor MHC-restricted) pathway in which CD4 T cells interact with MHC class II antigens expressed by donor APCs or 2) an 'indirect' (host MHC-restricted) pathway in which they interact with graft antigens processed and presented by host APCs in the context of class II MHC antigens. With these varied potential functions, the specific role the CD4+ T cell plays in allograft immunity or in tolerance induction remains undetermined. Alloreactive CD8+ T cell receptor (TCR) transgenic mouse models have demonstrated tremendous value in dissecting the role of the CD8 T cell in immune responses such as positive and negative selection, tolerance to peripheral antigens, autoimmunity and tumor immunity. Currently, there are no available alloreactive CD4+ TCR transgenic mice. Therefore, the specific aims of this project are to create TCR transgenic mice bearing CD4+ T cells activated via 1) the 'direct' (donor APC-dependent) and 2) the 'indirect' (host APC-dependent) pathways of alloantigen presentation. Such alloreactive CD4+ TCR transgenic animals would supply us with a renewable source of direct and indirect effector T cells of known specificity from which role of the CD4+ T cell in established models of islet allograft rejection and tolerance could be defined. They would allow critical evaluation of the hypothesis that: Both islet allograft immunity and tolerance are dependent on CD4 T cells that recognize graft antigen through indirect host MHC-restricted antigen presentation.